A novel SOD1 gene mutation in a Korean family with amyotrophic lateral sclerosis

BACKGROUND: Superoxide dismutase 1 (SOD1) gene mutations are responsible for approximately 20% of all familial amyotrophic lateral sclerosis (ALS) cases. However, these cases, especially those with SOD1 gene mutations, have not been reported in Korea. OBJECTIVES: The SOD1 gene in Korean family with ALS was screened for potential mutations and the clinical data was collected. MATERIALS AND METHODS: The clinical histories and neurological findings of the family members were obtained. Genomic DNA was isolated from the leukocytes of whole blood samples and the coding region of the SOD1 gene was analyzed by PCR and sequencing. RESULTS: The family with ALS showed a novel missense mutation in the SOD1 gene, which was heterozygous for the mutation, GGC to GTT, causing the substitution of valine for glycine at codon 10 (Gly10Val) in exon 1. Clinically, the patients exhibited early onset and rapid disease progression. CONCLUSIONS: Familial ALS with a novel Gly10Val mutation in the SOD1 gene showed severe clinical features. The mutation lies in a region involved in a dimer contact in the three-dimensional structure of the SOD1 protein. This study expands the number of ALS-associated SOD1 gene mutations.     

铜/锌超氧化物岐化物1突变致肌萎缩侧索硬化一家系分析并文献复习

目的探索一肌萎缩侧索硬化(ALS)家系基因突变位点并进行文献复习。方法对已知常见的ALS致病基因进行检测,进而对国内铜/锌超氧化物岐化物1(SOD1)基因突变型ALS进行文献复习。结果该家系患者平均起病年龄为(37.8±11.6)岁,均以肢体症状起病,平均病程约1.3年,死于呼吸衰竭。该家系SOD1基因4号外显子第305位存在AG突变(D102G)。目前国内报道的SOD1突变基因有26种。起病年龄最早者20岁,最晚者67岁;病程最短者仅1月,最长者达14年。86.4%的患者以肢体症状起病,4.5%以延髓症状起病,7.7%的患者以肢体和延髓症状起病。SOD1基因可表现为完全外显或不完全外显。结论 D102 G为国内首次报道的ALS疾病相关突变。不同SOD1基因突变位点临床症状具有异质性。     

中国家族性肌萎缩侧索硬化患者超氧化物歧化酶1基因突变分析

目的 肌萎缩侧索硬化(ALS)是上、下运动神经元退变引起的一种进行性致死性疾病,家族性ALS占10%～20%,铜锌SOD1基因突变存在于20%的家族性患者和少数散发性患者,某些突变还具有地域分布和特殊临床表型的规律性.我们旨在分析我国3个家族性ALS家系SOD1基因突变特点,并与不同国家和地区SOD1突变比较,分析其临床表型的特征性.方法 提取患者外周血基因组DNA,采用SOD1基因的5对引物对其5个外显子进行PCR扩增,产物直接测序.归纳整理患者临床表型资料,进行表型-基因型关联分析.结果 家系1中SOD1基因外显子2的H46R杂合突变,即CAT→CGT,使得46位由编码组氨酸变为编码精氨酸.先证者48岁,女性,43岁起病,主要表现为肢体无力和萎缩.家系中其他3例患者首发症状与先证者相似,病情进展均较缓慢,生存期较长.家系2中先证者20岁,男性,临床表现为延髓性麻痹,病程进展快速,生存期1年,位于3号外显子的杂合突变,即G72C突变.其父亲也出现同样的突变,但无ALS临床表现,其姑姑也有类似病史.家系3中5例患者5号外显子的E133V杂合突变,先证者中年起病,病程逐渐进展,生存期5年.结论 H46R的杂合突变国内未见报道,国外日本人曾多次报道及巴基斯坦有1个家系报道,欧美均未见报道,推测此突变可能为亚裔所特有.G72C突变的家系,临床表型为较早发病,病程进展迅速,生存期1年,突变外显率低导致家族成员不发病,常被诊断为散发病例,因此对于散发性患者及其家族成员同时检测SOD1基因突变十分必要.E133V突变的家系为国际首先报道.     

Comparison of the clinical and cognitive features of genetically positive ALS patients from the largest tertiary center in Serbia

Discovering novel mutations in C9orf72, FUS, ANG, and TDP-43 genes in ALS patients arises necessities for better clinical characterizations of these subjects. The aim is to determine clinical and cognitive profile of genetically positive Serbian ALS patients. 241 ALS patients were included in the study (17 familiar and 224 apparently sporadic). The following genes were analyzed: SOD1, C9orf72, ANG, FUS, and TDP-43. An extensive battery of classic neuropsychological tests was used in 27 ALS patients (22 SOD1 positive and 5 SOD1 negative) and 82 healthy controls (HCs). Overall 37 (15.4%) of 241 ALS patients carried mutations in tested genes—among 17 familiar ALS patients 16 (94.1%) were positive and among 224 apparently sporadic 21 (9.4%) had causative mutation. Mutations in SOD1 gene were the most common, representing 27 (73.0%) of all genetically positive ALS patients. The main clinical characteristics of SOD1 positive patients were: spinal onset in lower extremities, common sphincter and sensitive disturbances, and dysexecutive syndrome. Within SOD1 positive patients, we noticed somewhat earlier onset in patients with A145G, sensory and sphincter disturbances were dominant in patients with L144F, while D90A patients had significant sensory involvement. SOD1 negative group consisted of ten (27.0%) patients (six C9orf72, two ANG, one TDP-43, and one patient baring triple FUS, C9orf72 expansion, and ANG variants). Bulbar involvement and more extensive neuropsychological impairment (including executive, visuospatial, and memory difficulties) were the main features of SOD1 negative cohort. Our results suggest that meaningful clinical suspicion of certain ALS genotype might be made based on thorough clinical evaluation of patients.     

Detection of preclinical motor neurone loss in SOD1 mutation carriers using motor unit number estimation

OBJECTIVE: To determine the pattern of motor neurone loss in amyotrophic lateral sclerosis (ALS). In particular, to determine whether there is a gradual life long presymptomatic motor neurone loss or, alternatively, a sudden catastrophic loss just before the onset of symptoms. METHOD: The statistical motor unit number estimation (MUNE) technique was used in a longitudinal study of 19 asymptomatic carriers of the Cu, Zn superoxide dismutase 1 (SOD1) gene. MUNE results were compared with those of 34 age and sex matched SOD1 negative family controls and 23 population controls. Motor neurone loss was also estimated in 12 patients with sporadic ALS. 84 subjects (43 male and 41 female patients) with an age range from 16-73 years were followed up over three years, both clinically and by MUNE, every six months. RESULTS: In 2 of the 19 mutation carriers, there was a sudden reduction in MUNE several months before the onset of weakness. The patients with symptomatic sporadic ALS also had a reduced MUNE, but there was no detectable loss of motor neurones in the remainder of the subjects. CONCLUSION: MUNE can be used to detect preclinical loss of motor units in familial ALS. Normal numbers of motor neurones were maintained in 17 SOD1 mutation carriers over the three year period. There was an abrupt loss of motor neurones just before the onset of symptomatic weakness in two SOD1 mutation carriers. These results suggest that some form of trigger may initiate rapid cell loss and death of motor neurones just before the onset of symptoms.     

Clustering of ALS patients in central Italy due to the occurrence of the L84F SOD1 gene mutation.

OBJECTIVE: To study three new apparently unrelated Italian families with ALS and several sporadic ALS patients living in the same rural area. BACKGROUND: One Italian family with ALS carrying a superoxide dismutase 1 (SOD1) gene mutation (G41S) and no regional ALS clustering has been reported in Italy. METHODS: Genetic analysis was performed by automated and manual sequencing of the SOD1 gene in 13 family members and in 6 of 10 unrelated patients with sporadic cases of ALS living in the same area. The authors also determined SOD1 activity in erythrocytes and lymphocytes. RESULTS: The three families included a total of 28 affected members distributed over six generations. Despite a wide variability in age at onset and disease duration, the clinical pattern is uniform, with onset in the lower limbs, ascending progression, and predominant lower motor neuron involvement in all subjects. Generational anticipation is evident in the last two generations. All familial ALS patients and one of the six sporadic patients carry the same L84F missense point mutation in exon 4 of the SOD1 gene. SOD1 enzyme activity and SOD1 protein levels were not decreased significantly in the L84F patients. CONCLUSION: The ALS patients carrying the L84F mutation derive from a common ancestor. This mutation is responsible for ALS clustering in the area. The L84F mutation does not modify SOD1-specific activity.     

Mutational analysis of the Cu/Zn superoxide dismutase gene in a Catalan ALS population: should all sporadic ALS cases also be screened for SOD1?

BACKGROUND: SOD1 gene mutations are the most common identified cause of ALS, accounting for approximately 20% of familial ALS cases and around 4% of sporadic ALS cases. However, the prevalence of SOD1 varies in different ethnic groups. No previous epidemiological studies have been carried out in Catalonia. OBJECTIVE: To determine the prevalence of SOD1 gene mutations in a Catalan ALS population, and to analyze the genotype-phenotype relationship. MATERIALS AND METHODS: 30 different FALS pedigrees and 94 sporadic ALS patients were screened for SOD1 mutations using direct sequence analysis. RESULTS: Five of the 30 FALS pedigrees (16.6%) carried a SOD1 mutant. The mutations identified in this group were G37R, D76V, S105L, I112M and N139H. Four SOD1 mutants (4.25%) were found in the sporadic ALS group (SALS). The overall frequency (FALS plus SALS) of SOD1 mutations in our series was 6.45%. In the SALS group, D90A was identified in a patient presenting the typical Scandinavian phenotype. A 53-year-old woman with no family history of ALS carried the N139H mutation. Two unrelated sporadic ALS cases carried the A140A SOD1 mutant. CONCLUSIONS: The prevalence of the SOD1 mutation in FALS in Catalonia is similar to levels in other Mediterranean countries, but lower than those in reports studying the Belgian, Japanese, and Scottish populations. The prevalence of the SOD1 mutation was 4.25% in patients with no family history of ALS. These results may have significant repercussions on genetic counseling, and screening for the SOD1 mutation in sporadic ALS cases must therefore be considered.     

A novel exon 5 mutation (N139H) in the SOD1 gene in a Spanish family associated with incomplete penetrance

BACKGROUND: Allelic heterogeneity and phenotype variability-especially in age at onset, penetrance and progression-are reported in ALS1 families. For this reason, SOD1 gene mutation data in ALS1 patients are currently being gathered to better understand the genotype-phenotype relationship in this disorder. Here, we report the clinical and molecular characteristics of a Spanish ALS1 family with incomplete penetrance. PATIENTS AND METHODS: Clinical data including age at onset, initial topography, progression and survival were available in three affected members. Erythrocyte SOD1 activity was measured in four individuals. Analysis of the SOD1 gene was performed by PCR and direct sequencing. RESULTS: A novel missense mutation in the exon 5 of the SOD1 gene, an A-to-C transversion at nucleotide position 1485 leading to N139H residue change, was identified in three family members. The phenotype was similar in all cases, with initial symptoms in the distal limb muscles and a mean survival time of around 4 years. Incomplete penetrance was observed in our family, as two obligate carriers did not develop any symptoms of amyotrophic lateral sclerosis (ALS). CONCLUSIONS: N139H is the fifth SOD1 gene mutation reported in Spain, and the first one presenting with incomplete penetrance. Genetic counseling for at-risk relatives in these low-penetrance families could be difficult as some individuals harbouring the mutation remain asymptomatic throughout their lives. Further genetic characterisation of ALS1 families should provide information regarding the distribution of SOD1 mutants in different ethnic groups.     

Superoxyde dismutase 1 gene abnormalities in familial amyotrophic lateral sclerosis: phenotype/genotype correlations. The French experience and review of the literature

About 20 p. cent of cases of amyotrophic lateral sclerosis are familial (FALS). Fifteen percent of FALS cases are associated with an abnormality in the superoxide dismutase 1 (SOD1) gene. To date, more than 100 different genetic abnormalities have been reported, all except two are autosomal dominant. The clinical characteristics of patients presenting with FALS associated with an SOD1 abnormality is homogeneous when there is no doubt about the hereditary aspect of the genetic abnormality: mean age at onset 42 years, limb onset, slow evolution. Except when present in the setting of a clearly inherited disease (FALS) (several patients through several generations), the causality of a given SOD1 mutation often remains an open question. Consequently, search for SOD1 mutation is not warranted when atypical features such as young age at onset or slow progression are present. Conversely, a complete family study is justified to determine the precise role of a given SOD1 mutation because of the large number of potential SOD1 mutations, the variability of the transmission mode, and the non-exceptional absence of proven causality for ALS. Specific cases where a frequent SOD1 mutation with a recognized causal effect is recognized (no more than 15 out of more than 90 mutations) would be an exception.     

The G93C mutation in superoxide dismutase 1: clinicopathologic phenotype and prognosis

BACKGROUND: Twenty percent of familial amyotrophic lateral sclerosis (ALS) is caused by mutations in the superoxide dismutase 1 gene (SOD1). Few data exist on their clinicopathologic phenotypes. OBJECTIVES: To determine the clinical and pathologic phenotype associated with the G93C mutation in SOD1 and to compare survival in familial ALS related to this mutation with survival in other ALS subgroups. DESIGN: Retrospective study. SETTING: Tertiary referral center for neuromuscular disorders. PATIENTS: Twenty patients with the G93C mutation for whom clinical data were available and 1 patient with pathologic data. MAIN OUTCOME MEASURES: Characteristics and survival compared with other ALS subgroups, adjusting for known prognostic factors. RESULTS: The G93C mutation was associated with a purely lower motor neuron phenotype without bulbar involvement. Presence of the mutation independently predicted longer survival compared with other ALS subgroups. Pathologic examination showed degeneration of the anterior horn, spinocerebellar tracts, and posterior funiculi, with minimal involvement of corticospinal tracts and no degeneration of brainstem motor nuclei. Survival motor neuron gene copy number had no significant influence on age at onset or survival in patients with the G93C mutation. CONCLUSIONS: These findings add to the knowledge of SOD1-related familial ALS and demonstrate further clinicopathologic variability between different SOD1 mutations. Finally, they demonstrate the independent prognostic value of the G93C mutation.     

Confirmation of the severe phenotypic effect of serine at codon 41 of the superoxide dismutase 1 gene

Introduction: A Gly41Ser mutation in the superoxide dismutase 1 gene (SOD1) has been reported to cause a very rapid course of amyotrophic lateral sclerosis (ALS) in a limited number of Italian patients, but a Gly41Asp mutation results in a more benign course. Methods: Four members of an African American family with autosomal dominant ALS were evaluated clinically over 12 years. Mutation analysis of SOD1 was done on 1 patient. Results: All patients had a pure lower motor neuron syndrome with onset to death in 9–15 months. A Gly41Ser mutation in SOD1 was established. In silico modeling suggested that this mutation can have a more deleterious effect than a Gly41Asp mutation. Conclusion: The more rapid course of ALS with the Gly41Ser SOD1 mutation is confirmed in a distinct ethnic group. Muscle Nerve, 2011     

Clinical characteristics of SOD1 gene mutations in UK families with ALS.

Five to ten percent of patients with ALS have a family history of the disease, inheritance is usually autosomal dominant. Mutations of the SOD1 gene were first identified in a proportion of families with ALS by Rosen et al. The SOD1 gene encodes the enzyme copper zinc superoxide dismutase. Patients were studied from throughout the UK, where more than one individual in the family had ALS. Clinical history and examination of the individual and family were obtained, and DNA extracted from leukocytes of whole blood samples. Mutations were identified by standard sequencing methods. To date, 12 different mutations of SOD1 have been identified in 17 different families, representing around 20% of all ALS families studied. The mutations were mainly single base substitutions - H48Q, G72S, G93R, G93V, E100G, D101N, D101G, G108V, I113T, D125H, I149T - and also an insertion mutation - 132insTT - leading to a premature stop codon. The mutations were present in exons 2-5. We did not identify mutations in exon 1, although these have been identified by others in different patient samples. We have identified SOD1 mutations in around 20% of UK families with ALS studied. This is similar to that reported in other populations. Mutations have now been identified in all exons of SOD1. The individual mutations do not precisely predict disease severity, and generally it is difficult to give a specific prognosis based on the individuals' SOD1 mutations. We continue to investigate the possible pathogenic mechanisms of the SOD1 mutations. We have studied the neuropathology in patients with SOD1 mutations. We are also performing linkage studies to identify the genes involved in the 80% of families where an SOD1 mutation has not been identified.     

The epidemiology of CuZn-SOD mutations in Germany: a study of 217 families

We screened 217 patients from Germany (n = 213), Austria (n = 2) and Switzerland (n = 2) with a positive family history for amyotrophic lateral sclerosis (ALS) for mutations in the copper/zinc superoxide dismutase (SOD1) gene. We found that 13% of the families tested carried mutations. By analyzing inheritance, we detected a clear-cut co-segregation in 5 of the 28 families; however, in two families with an established mutation, co-segregation was absent. In Germany, the R115G mutation is comparatively frequent and exhibits a specific aggressive phenotype. The L144F mutation, which is the most prevalent mutation in the Balkan countries, and the D90A mutation which is the most frequent SOD1 mutation globally, seem to be the second most common disease-causing mutations in Germany.     

Normal complement of motor units in asymptomatic familial (SOD1 mutation) amyotrophic lateral sclerosis carriers

OBJECTIVE: To understand the mechanisms causing neuronal death in amyotrophic lateral sclerosis (ALS), an electrophysiological technique of motor unit number estimation (MUNE) was used to examine the pattern of motor neuron loss in amyotrophic lateral sclerosis. The aim was to determine whether gradual lifelong loss of motor units precedes clinical disease or whether sudden, catastrophic loss of motor units occurs at the onset of the disease. METHOD: Using the statistical technique of motor unit number estimation, a cross sectional study was performed on a group of asymptomatic carriers of the Cu, Zn superoxide dimutase 1 (SOD1) gene. MUNE results were compared with those from age and sex matched family controls who did not carry the SOD1 mutation. A total of 87 subjects (45 men and 42 women) with an age range from 16-73 years of age were studied. RESULTS: There was no detectable difference in the number of motor units in SOD1 mutation carriers compared with SOD1 negative family controls or population controls. Symptomatic subjects showed a definite loss of motor units. The test-retest reproducibility of this technique yielded an average difference between MUNE results on separate occasions on the same subject of +/-5%. CONCLUSION: The finding that presymptomatic SOD1 mutation carriers have a full complement of motor neurons indicates that mutation carriers must have normal survival of motor neurons until rapid and widespread cell death of these neurons occurs, coinciding with the onset of clinical features. This implies that symptomatic ALS is not the end result of a slow attrition of motor neurons.     

Molecular analysis of the superoxide dismutase 1 gene in Spanish patients with sporadic or familial amyotrophic lateral sclerosis

We performed a genetic analysis of the Cu/Zn superoxide dismutase gene (SOD1) in Spanish patients with sporadic or familial amyotrophic lateral sclerosis (ALS). We found mutations in 2 of 11 families (18%) with ALS. In addition, 1 of the 87 sporadic ALS patients studied harbored a mutation in the same gene. We identified G37R in exon 2 of the SOD1 gene in 1 family. Another patient, with sporadic ALS, showed a novel N65S in exon 3. In addition, we found a novel I112M in exon 4 in another family. Our data highlight the genetic heterogeneity of patients with ALS harboring mutations in the SOD1 gene and confirm that families with autosomal dominant inheritance of the trait, regardless of their ethnic background, are more likely to carry mutations in such a gene.     

Superoxide dismutase gene mutations in Italian patients with familial and sporadic amyotrophic lateral sclerosis: identification of three novel missense mutations

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting motor neurons. The majority of the patients are sporadic cases (SALS), while 5-10% of the patients have a family history of ALS (familial ALS or FALS). Mutations in the gene coding for cytoplasmic Cu/Zn superoxide dismutase (SOD1) have been identified in about 20% of FALS cases. We found SOD1-gene mutations in five of 34 unrelated FALS, and in two of 44 SALS patients. Three FALS patients carried the previously described A4V (two cases) and L84F mutations (one case), while two FALS patients carried new missense mutations: a G12R substitution in exon 1, and a F45C substitution in exon 2, respectively. The newly identified mutations were both associated with a slowly progressive disease course. Two SALS patients carried the homozygous D90A and the heterozygous I113T mutation, respectively. In addition, in one SALS patient we identified an A95T amino acid substitution, that is apparently a non-pathogenic SOD1 variant. Our study increases the number of ALS-associated SOD1 gene mutations.     

Identification of two novel mutations in the Cu/Zn superoxide dismutase gene with familial amyotrophic lateral sclerosis: mass spectrometric and genomic analyses

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting motor neurons. The majority of patients are sporadic cases, while 5-10% of the patients have a family history of ALS (fALS). Mutations in the gene that encodes cytoplasmic Cu/Zn superoxide dismutase (SOD1) have been identified in about 25% of fALS cases. Although the precise pathogenesis of ALS is still unknown, experimental studies including animal models suggest that fALS is caused by the toxic gain-of-function of the SOD1 mutant. We have analyzed not only SOD1 gene mutation by genomic sequencing, but also SOD1 mutant protein by liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS). We analyzed 33 fALS patients and found 10 mutations in SOD1 gene, in which two were novel: Asp101His substitution in exon 4 and Gly141Glu substitution in exon 5. Here, we present their mass spectrometric protein analyses and clinical features.     

Compound heterozygous D90A and D96N SOD1 mutations in a recessive amyotrophic lateral sclerosis family

We describe a French amyotrophic lateral sclerosis (ALS) family with two distinct mutations in the Cu/Zn superoxide dismutase (SOD1) gene. The D90A mutation has been well described and clearly shown to cause recessive ALS. In this family, affected individuals are heterozygous for the D90A mutation and also carry a single copy of a novel SOD1 mutation, D96N. We propose that in this family both mutations are required for the development of disease.     

A Japanese familial ALS patient with autonomic failure and a p.Cys146Arg mutation in the gene for SOD1 (SOD1)

We describe a Japanese man with familial amyotrophic lateral sclerosis (ALS) associated with a p.Cys146Arg mutation in the copper/zinc superoxide dismutase gene (SOD1). The patient developed bulbar signs followed by rapidly progressive limb muscle weakness. The prominent clinical feature was orthostatic hypotension due to autonomic failure, which occurred after he underwent tracheostomy 1 year and 3 months after the onset. Thereafter, he required mechanical ventilation and progressed to communication stage V (totally locked‐in state) 7 years after the onset. Neuropathology showed ALS with posterior column degeneration and multiple system degeneration. Severe neuronal loss in the intermediolateral nucleus was also observed. Two previously reported cases of ALS patients with autonomic failure showed severe neuronal loss in the intermediolateral nucleus in addition to degeneration of the motor neurons. Thus, autonomic failure due to neuronal loss in the intermediolateral nucleus could present in patients with ALS associated with certain mutations in SOD1.     

AGE DEPENDENT PENETRANCE OF THREE DIFFERENT SUPEROXIDE DISMUTASE 1 (SOD 1) MUTATIONS

The age of onset of motor neuron disease in Cu/Zn superoxide dismutase 1 (SOD1) mutation carriers are variable, commencing at any time from the second decade. The authors performed a retrospective analysis of family information in pedigrees dating back to the 1780s, to determine the age-dependent penetrance of three different SOD1 mutations: Glu100Gly, Ile113Thr, and Val148G1y. The penetrance of symptomatic MND in these three SOD1 mutations was greater than 95% by the age of 78. The affected family members with the Val148Gly mutation had the worst prognosis, with a mean age of death of 46.1 years, compared to 54.2 years for the Glu100Gly mutation and 59.9 years for Ile113Thr mutation. Kaplan-Meier survival curves showed that survival of the 3 SOD1 mutation families, when combined, was reduced by nearly 10 years with the mean age of death for all SOD1 mutation carriers being 52.6 years compared to 62.5 years for the control individuals. The SOD1 mutation group also resulted in earlier death compared to sporadic MND, which from natural history studies is 61.4 years. This may reflect that the SOD1 mutation is associated with more progressive and rapid disease, as the age of onset of disease was not earlier. This information would have important implications for genetic counseling of members of individual SOD1 mutation carrier families.